Flu virus weak spot found by Scripps Research scientists

This graphic depicts influenza infection. A viral protein called hemagglutinin binds to the sialic acid receptors on the surface of a human respiratory tract cell. The structure of hemagglutinin fits the sialic acid receptors like Velcro. Once virus is attached to the cell, it is then able to enter and infect the cell. This marks the beginning of a flu infection.
— Centers for Disease Control and Prevention, National Center for Immunization and Respiratory Diseases (NCIRD)

This graphic depicts influenza infection. A viral protein called hemagglutinin binds to the sialic acid receptors on the surface of a human respiratory tract cell. The structure of hemagglutinin fits the sialic acid receptors like Velcro. Once virus is attached to the cell, it is then able to enter and infect the cell. This marks the beginning of a flu infection.
/ Centers for Disease Control and Prevention, National Center for Immunization and Respiratory Diseases (NCIRD)

Once docked with the sialic acids, the virus injects itself into cells. The protein’s attachment sites mutate rapidly, making new vaccines necessary each year.

The cavity is found at the “head” of this flu protein, called hemagglutinin, where the attachment occurs. Unlike many other parts of the virus, this cavity doesn’t change, Wilson said. That fact suggests the cavity’s structure is important to the virus.

“This is extremely promising work, as it suggests a way that one could produce a drug or design a vaccine, that essentially corners this perpetual moving target so that all that can evolve are noninfectious progeny,” Cohen and Gagneux wrote in an email.

“This new discovery does provide a new molecular scaffold on which to base the designing of potential drugs that efficiently block the binding of a broad variety of influenza A viruses, including viral strains from bird hosts, which represent an eternal reservoir for these viruses in the wild.”

Cohen and Gagneux said drugs developed from this approach could cause fewer side effects than Tamiflu, which targets a complementary viral protein, called neuraminidase. While hemagglutinin brings flu viruses into cells, neuraminidase causes newly formed flu viruses to be released from infected cells.

"Humans have their own neuraminidase enzymes with important roles in immunity, fertilization and brain function, possibly opening up side effects of neuraminidases," they wrote. " In contrast humans do not have hemagglutinin-like proteins, making hemagglutinin a very promising drug target."

Three human antibodies (8F8, 2G1 and 8M2) block the binding site of influenza virus hemagglutinin (in colored surface). These antibodies connect to a part of the binding site that varies little among strains, or as scientists say, is "highly conserved". This finding suggests a new strategy for producing a drug that can work against many flu strains, with less of a chance that the virus can escape by mutation and still remain infections.
— Ian Wilson lab, The Scripps Research Institute

Three human antibodies (8F8, 2G1 and 8M2) block the binding site of influenza virus hemagglutinin (in colored surface). These antibodies connect to a part of the binding site that varies little among strains, or as scientists say, is "highly conserved". This finding suggests a new strategy for producing a drug that can work against many flu strains, with less of a chance that the virus can escape by mutation and still remain infections.
/ Ian Wilson lab, The Scripps Research Institute

Hemagglutinin links with numerous sialic acid molecules on the cell surface. By themselves, these attachment sites are weakly binding, but together they tightly bind the virus to cells, “like Velcro,” Wilson said, using the same analogy as Cohen and Gagneux.

The body responds to this viral invasion, or to flu vaccines, by producing antibodies, large protein molecules. These antibodies latch onto the various viral attachment sites — the Velcro — getting in between the virus and the cells. But these sites mutate rapidly.

So Wilson and his collaborators looked to clues from nature to find “broadly neutralizing” antibodies that showed success against many flu strains. He found three such antibodies, all of them attaching to this particular cavity.

Because the cavity doesn’t change shape when the virus mutates, the attachment creates a physical blockage that the virus can’t evade, except by losing its sialic acid attachments, Wilson said. Since these attachments are the only way it can grab onto human cells, the mutated virus can’t infect people.

These broadly neutralizing antibodies share a characteristic formation that allows them to thrust a narrow arm deep into the viral protein. Wilson said that is important, because this formation allows the antibodies to avoid the highly mutable bumps and protrusions around this vulnerable site that block most antibodies from attaching.

Other authors of the paper were Ryan McBride and James C Paulson of Scripps, and Jens C Krause and James E Crowe Jr. of Vanderbilt University Medical Center, Nashville, Tennessee.